1. Field of the Invention
The present invention relates generally to carboline derivatives. In particular the present invention relates to 1-substituted 1,2,3,4-tetrahydro-xcex2-carboline and 3,4-dihydro-xcex2-carboline derivatives which may have useful therapeutic activity, particularly anti-mitotic activity. The present invention also relates to the use of these compounds in therapy and to compositions containing them.
2. Background Art
Despite the increasing research efforts directed towards their treatment and cure, cancerous conditions remain one of the major causes of human mortality. Current clinical treatments include radiation or chemotherapy, or combinations of both. However, in many cases chemotherapy plays a vital role in cancer treatment. The development of various chemotherapeutic drugs which are presently in clinical use has generally been on the characterization of the proliferative cancer cells. The effect of these drugs is to inhibit proliferation of the cancer cells. The chemotherapeutic drugs which are currently used in clinics can be classified into five groups according to their mechanisms of action. They are: (1) alkylating agents, (2) antimetabolites, (3) antibiotics, (4) steroids, and (5) plant alkaloids. The effect of first four groups is considered to occur at the DNA level. The effect of the last group, plant alkaloids, is considered to occur at protein level. During cell proliferation, the chromosome segregation is towed by the mitotic spindle. Therefore, disrupting the formation of the mitotic spindle, can inhibit cell proliferation. Compounds which inhibit cell proliferation by disrupting the formation of the mitotic spindle are called antimitotic agents.
The mitotic spindle is a microtubule-based structure and a cytoskeleton protein. In addition to forming the spindle fibre at mitosis, the mitotic spindle is also involved in intracellular transport, motility architecture (Dumontet, C. et al, J. Clin. Oncol., 17(3), 1061-1070, 1999 and Alberts, B., et al, Molecular Biology of the Cell, 3rd xe2x80x9cEdition, 807-813, 1994). Microtubules are composed of xcex1, xcex2, tubulin dimer and microtubule associated proteins. The microtubule structure is a dynamic structure with a rapid turnover rate, its half-life being only about 10 minutes. The polymer and tubulin dimer are always in an unstable equilibrium with polymerisation and depolymerisation of microtubules continually and dynamically taking place. The process must go through a course of nucleation, when the tubulin dimer polymerises into a microtubule. In most cells the centrosome is the center of microtubule organizations. After nucleation, polymerisation (lengthening) starts along the cellular periphery. Depolymerisation (shortening) will then occur shortly after polymerisation (it shrinkages back to centrosome). This can result in partial depolymerisation of microtubules that revert to a polymerisation status or the disappearance and replacement with a new microtubule. The process of alternate polymerisation and depolymerisation is called dynamic instability, and this plays an important role in microtubule function. For instance, some proteins inhibit dynamic instability of microtubules thereby inhibiting depolymerisation when cells differentiate into certain morphologies. Mitosis and cytokinesis of normal cells also depend on dynamic instability. Both of rates of polymerisation and depolymerisation of microtubules accelerate at M phase. During mitosis, microtubules rapidly assemble the mitotic spindle. The mitotic spindles subsequently disassembles along the pores of spindle to complete mitosis. Thus, disruption of the dynamic instability of the microtubules, call prevent mitosis and cellular proliferation. The new direction for cancer treatment research is to find new drugs that disrupt the dynamic instability of microtubules.
At present, the antimitotic agents used in the clinic include colchicine, vinca alkaloids and taxol. All of these are natural products. Colchicine and vinca alkaloids can stimulate microtubule depolymerisation. However, the cytotoxicity of colchicine towards healthy cells restricted its development as a widespread therapeutic and its current use is in the treatment of gout. Taxol also disrupts the dynamic instability of the microtubular structure but acts in an opposite manner to colchicine by stimulating tubulin polymerisation and stabilizing microtubules. Many of the antimitotic agents currently under investigation, such as combratastatins, curacins, dolastatin 10, 15, cryptophycins, exhibit antiproliferative mechanisms similar to colchicine or vinca alkaloids. A few, such as discodermolide, epothilones, eleutherobin and laulimalides, exhibit taxol-like effects.
Marine natural products which contain a xcex2-carboline skeleton are widely distributed in marine invertebrates (Blackman, A. J., et al, J Nat. Prod., 1987, 50, 494; Kearns, P. S., et al, J Nat. Prod., 1995, 58, 1075; Kobatashi, J., J Nat. Prod., 1994, 57, 1737). A number of these have been shown to exhibit antitumor and antiviral activity. Particularly interesting compounds include the eudistomins (Badre, A., et al, J Nat. Prod., 1994, 57, 528 and Rinehart Jr, K. L., et al, J Am., Chem. Soc., 1987, 109, 3378) and manzamines (Crews, P., et al, Tetrahedron, 1994, 50, 13567 and Sakai, R., et al Tetrahedron, 1987, 28, 5493) which were isolated from marine tunicates and sponges, respectively. As a class, the oxathiazepine containing eudistomines exhibited potent inhibitory activity toward DNA virus HSV-1. In addition, the antiviral eudistomines C (1) and E (2) were also found active against HSV-2, the Vaccinia virus and RNA viruses. The novel structures of manzamines, however, were reported to possess potent antitumor activity (Ichiba, T., et al, Tetrahedron Lett., 1988, 29, 3083 and Higa, T., Studies in Natural Product Chemistry, Vol. 5, Part B, Elsevier Co., New York, 1989, pp346-353). The most active was manzamine A (3), a principal metabolite from several species of sponges, which showed cytotoxicity against murine P-388 cells at 0.07 xcexcg/ml (Sakai, R., et al, J Am. Chem., Soc., 1986, 108, 6404). 
1-Substituted 1,2,3,4-tetrahydro-xcex2-carboline and 3,4-dlhydro-xcex2-carboline derivatives have now been prepared and have been shown to exhibit biological activity.
These compounds may, therefore, be useful in the treatment of cancerous conditions.
Throughout the specification and the claims which follow, the word xe2x80x9ccomprise,xe2x80x9d and variations such as xe2x80x9ccomprisesxe2x80x9d and xe2x80x9ccomprising,xe2x80x9d will be understood to imply the inclusion of a stated integer, element, or step, or group of integers, elements, or steps, but not the exclusion of any other integer, element, or step, or group of integers, elements, or steps.
In a first aspect, the present invention provides a compound of formula (I). 
wherein  is an optional double bond, Y comprises one selected from hydroxy, C1-6 alkoxy, benzyloxy, C1-6 acyloxy, amino, C1-6 alkyl, C1-6 dialkylamino, halogen and carboxy, and n is 0, 1, 2, 3, or 4, and R comprises one selected from the group consisting of an optionally substituted carbocyclyl (xe2x80x9ccarbocyclicxe2x80x9d) group or an optionally substituted heterocyclyl (xe2x80x9cheterocyclicxe2x80x9d) group; or a salt or prodrug thereof.
In another aspect, the invention relates to a composition comprising a compound according to formula (I), or a salt or prodrug thereof, together with a pharmaceutically acceptable carrier, diluent or excipient.
In yet another aspect, the invention relates to a method for the treatment of a cancerous condition comprising the administration of a treatment effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof, to a subject in need of said treatment.
The invention further provides for the use of a compound of formula (I), or a salt or prodrug thereof, in the manufacture of a medicament for the treatment of a cancerous condition.
The invention also provides an antitumor agent comprising a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.
Other aspects and advantages of the invention will be apparent from the following description and the appended claims.